July 2, 2012

Reversible Lithium Neurotoxicity: A Review

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Ivan Netto, MD, and Vivek H. Phutane, MD

Parmar Plaza Clinic, Fatimanagar, Pune, Maharashtra, India (Dr Netto) and Yale University School of Medicine, New Haven, Connecticut (Dr Phutane)


See related article.

Lithium is an efficacious treatment, especially for the prophylaxis of bipolar mood disorders. Adverse events with lithium occur on a continuum from simple side effects to early reversible neurotoxicity to irreversible neurotoxicity. The clinical features of irreversible lithium neurotoxicity are permanent and easier to detect than those of reversible lithium neurotoxicity. In cases of reversible lithium neurotoxicity, patients recover without any permanent neurologic sequelae, even after 2 months of an episode of lithium toxicity. Our review in The Primary Care Companion for CNS Disorders described the clinical profile, precipitating factors, and preventive measures for reversible lithium neurotoxicity.

The following clinical profile emerged after our evaluation of 52 cases of reversible lithium neurotoxicity. Like irreversible neurotoxicity, reversible neurotoxicity appears to have no specific correlation with age or sex. Reversible lithium neurotoxicity was observed in all age groups, and a greater number of reported patients were female. Most patients had diagnoses of affective disorders, schizoaffective disorder, and depression. Reversible toxicity usually occurred when lithium carbonate doses were in the therapeutic range of less than 2,000 mg/day (without any reported overdoses) and when serum lithium levels were below 1.5 mEq/L. Conversely, most cases of irreversible lithium neurotoxicity involve levels above the therapeutic range, and some doses are even fatal or dangerously high due to suicidal intent.

The common physical clinical features of reversible lithium neurotoxicity were mainly pyramidal, extrapyramidal, and reversible cerebellar neurologic signs. Permanent choreoathetosis and peripheral neuropathies, which are features of irreversible lithium neurotoxicity, were not seen. The common mental clinical features of reversible lithium neurotoxicity were mainly those of an acute brain syndrome (delirium), whereas those of irreversible lithium neurotoxicity present as a chronic brain syndrome that requires rehabilitation.

Common precipitating factors for reversible neurotoxicity were antipsychotic or other drug combinations with lithium, underlying brain pathology, and abnormal tissue levels (especially in elderly patients or those with acute mania and prominent psychotic symptoms and anxiety). In some cases, the precipitating factor could not be ascertained.

The examination that most often produced abnormal results in patients with lithium neurotoxicity was the EEG. Other tests often produced normal findings despite neurotoxicity. Monitoring diffuse slowing of the EEG appears to be useful in detecting early lithium neurotoxicity.

We hope that our review will help in the prevention of permanent lithium neurotoxicity by encouraging conservative prescribing, careful monitoring, care in combining other drugs with lithium, early detection, prompt management, and proper psychoeducation of patients and caregivers. We look forward to working with researchers in this field.

Financial disclosure:Drs Netto and Phutane had no relevant personal financial relationships to report. ​

Category: Bipolar Disorder
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21 thoughts on “Reversible Lithium Neurotoxicity: A Review

  1. I have only seen it when the lithium is mixed with antipsychotics especially haloperidol. Can neurotoxicity occur without the antipsychotic combination?
  2. Lithium neurotoxicity has been observed with antipsychotics such as haloperidol, thioridazine, clozapine, risperidone and also without the antipsychotic combination.
  3. The pyramidal tracts refers to the corticospinal and corticobulbar tracts. Pyramidal side effects may include spasticity, decreased vigor (and increased threshold) of superficial reflexes, a loss of the ability to perform fine movements, and an extensor plantar response known as the Babinski sign.
  4. I suffered irreversible lithium neurotoxicity in 1987. I took 2 doseages on succeeding days of 900mg and 1200mg. This was mixed with doxycycline. I started suffering a L inferior orbicularis fasciculation that lasted for a couple of days. I stopped all medication. 2-3 days later with the fasciculation still present I was prescribed naprosyn. About 2 days later I started having fasciculations from head to toe. Big ones and little ones. I also developed a lithium tremor. About 3 weeks later I developed dysthesthesiae diffusely without missing a dermatome. It has a sympathetic component and I go numb easier. So, that’s how you can do it. The sympathetic response comes with goose flesh.
  5. West et al has reported that acute mania with marked psychotic symptoms and intense anxietymay be associated with increased vulnerability to the development of severe lithium neurotoxicity.
    Ref:West AP, Meltzer HY. Paradoxical lithium neurotoxicity:
    a report of five cases and a hypothesis about risk for
    neurotoxicity. Am J Psychiatry. 1979;136(7):963–966.
  6. General slow wave activity & mild diffuse disturbance with theta – Bell et al 1993,
    sharp spikes and slow waves activity bi-temporal & grossly abnormal sharp waves and spikes more Rt. temporal- Spring et al 1979, diffuse and rhythmic slowing especially in fronto-temporal region – Kemperman et all 1987, slow dominant rhythmic with fast rhythm and periodic sharp waves occasional delta waves – Smith et all 1988, periodic complexes & slowing -Broussolle et all 1989, slow waves with delta activity – Finelli et al 1992
  7. Preventive measures to prevent Lithium neurotoxicity

    Lithium + neuroleptics combination is useful but to be used with

    Haloperidol in high doses + lithium for the control of severe manic excitement to be used with caution

    Strict monitoring of clozapine + lithium combination
    For thioridazine + lithium, a baseline and subsequent follow-up EEG monitoring have been are recommended.

    Neurotoxicity on therapeutic serum lithium levels should alert the clinician to the possibility of a treatable intracranial

    A subclinical encephalopathy in patients with alcoholism can lead to neurotoxicity

    All patients suspected to have pseudotumor cerebri due to receiving lithium should have a fundoscopy examination done and an inquiry
    should be made regarding the history of receiving
    lithium treatment

    Fluctuating serum lithium levels which may point to the possibility of abnormal tissue levels.

    Caution has been recommended when lithium is used in the elderly population.

    Manic patients with prominent psychotic symptoms and intense anxiety are more prone for lithium neurotoxcity.

    Caution about the possibility of a serotonin-like syndrome when lithium is combined with fluoxetine has been highlighted, although the
    combination is not contraindicated.

    Periodic sharp waves detected by serial EEGs in patients receiving lithium should alert the clinician to the possibility of neurotoxicity

    A careful history of receiving lithium treatment in all patients who present with a rapidly progressive dementia and EEG findings suggestive of a Creutzfeld- Jacob –like syndrome to prevent lithium toxicity and to avoid expensive, unnecessary neurologic investigations
    and invasive procedures such as brain biopsy

    Recommends the use of both serum lithium and red blood cell RBC lithium levels

  8. Any comments on neurotoxicity Li combined with ECT treatments?
    Collegues seem to conflict on usage of Li during ECT in regard to lessening memory loss and neurotoxicity.
  9. Li + Haloperidol – probably increased intracellular concentration of Li Ref.33- Coffey et al

    Li + thioridazine
    strong dopamine blocking effect Ref. 26-Spring et al

    Li + risperidone
    increased dopamine receptor blockage and increased intracellular lithium Ref.36- Boora et al

    Li+ clozapine
    serotonergic effects of the combination Ref. 34, 35 – Blake et al

  10. 1. J ECT. 2005 Sep;21(3):165-70.

    The safety of electroconvulsive therapy and lithium in combination: a case series
    and review of the literature.

    Dolenc TJ, Rasmussen KG.

    Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota 55905,

    Early reports cautioned against the combination of lithium and electroconvulsive
    therapy (ECT), citing risk of excessive cognitive disturbance, prolonged apnea,
    and spontaneous seizures. However, recent case series with larger numbers of
    patients indicate that the combination may be used safely and with optimal
    efficacy in certain clinical circumstances. In this report, we describe 12
    patients in whom the combination of lithium and ECT was deemed safe. We also
    provide a comprehensive review of published literature and provide detailed
    recommendations for clinical practice.

    2. Negative interaction between lithium and electroconvulsive therapy–a case-control study.
    A K Jha,
    G S Stein and
    P Fenwick
    Department of Psychiatry, Farnborough Hospital, Kent.
    BACKGROUND Concurrent use of lithium and ECT is suspected to increase neurotoxicity.
    METHOD A retrospective case-control study over an eight-year period was conducted to investigate the adverse effects of a combined lithium/ECT treatment. Thirty-one subjects with combined lithium/ECT treatment were compared with a control group (ECT only) of 135 cases matched for age and sex.
    RESULTS Most cases in both groups had no adverse effects. Three (10%) study group subjects and 15 (11%) controls experienced brief delirium. Three controls and none of the subjects developed a prolonged confusion. There were no significant differences in the profile of other adverse effects between the two groups.
    CONCLUSION Prescription of lithium together with ECT was not associated with higher frequency of adverse effects.

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